Disease relevance of PPET-1

• Regional variability in preproEndothelin-1 gene expression in sheep pulmonary artery and lung during the onset of air-induced chronic pulmonary hypertension. Participation Of arterial smooth muscle cells [1].
• ET-1 levels in coronary sinus blood before ischemia and at 0 and 30 minutes of reperfusion in 8 control hearts were constant (2.2 +/- 1.2 fmol/L, 2.2 +/- 1.3 fmol/L, and 2.5 +/- 1.0 fmol/L, respectively) [2].
• When ET1 (10 pmol/kg body weight) was injected together with PTHrP-(1-86) (100 pmol/kg body weight), only a significant increase in mammary blood flow was observed [3].
• It has been suggested that ET-1 may have a role in the airway smooth muscle hyperplasia and hypertrophy seen in patients with bronchial asthma [4].
• Blood levels of ET-1, which rose with hypoxia but not ONO-11113 treatment, were not changed by either antagonist [5].

High impact information on PPET-1

• Smooth muscle cells (SMC) isolated from the main and midregion artery of control sheep confirmed these findings and showed higher levels of intracellular ET-1 synthesis in the main versus the midregion artery [1].
• In main pulmonary artery and lung, ppET-1 transcripts fell to < 1% of controls [1].
• We conclude that SMC from the main and midregion pulmonary artery are phenotypically different and suggest that local synthesis of ET-1 and TGF-beta, and increased levels of ET-1 in lung lymph, regulate ppET-1 gene expression and synthesis in arterial SMC during the development of air-induced CPH [1].
• A semiquantitative reverse transcription PCR for ppET-1 gene expression was developed using ovine-specific primers [1].
• CONCLUSIONS: These results, combined with prior studies, suggest that I/R causes reduced production of endogenous vasodilators (eg, nitric oxide), leaving unopposed the vasoconstriction that is caused by the continued presence of ET-1 [2].

Chemical compound and disease context of PPET-1

• METHODS AND RESULTS: We measured plasma ET-1 concentrations by radioimmunoassay in isolated blood-perfused neonatal lamb hearts before and after 2 hours of 10 degrees C cardioplegic ischemia and examined the effects of ET-1 and the endothelin-A (ET-A) receptor antagonist BE-18257B on the postischemic recovery of isolated hearts [2].
• We conclude that during sepsis, the NO scavenger PHP unmasks an underlying ET-1 mediated vasoconstriction, and its effect is antagonized by L-arginine and bosentan [6].
• To investigate the role of endothelin-1 (ET-1), a potent vasoconstrictor produced by vascular endothelium, in HPVR an in vivo model of alveolar hypoxia was developed [7].
• During U46619-induced pulmonary hypertension, both 4 Ala ET-1 (3.2% +/- 8.0 to 15.9% +/- 6.4, p < 0.05) and IRL 1620 (8.7% +/- 6.3 to 21.9% +/- 4.1, p < 0.05) produced selective dose-dependent decreases in PAP [8].
• Phosphoramidon inhibits bET-1-induced hypertension, suggesting that the fetus possesses ET-1-converting enzyme activity [9].

Biological context of PPET-1

• The ET-1 hearts showed significantly reduced recovery of LV systolic (positive maximum and volume-normalized dP/dt) and diastolic (negative maximum dP/dt) function, CBF, and myocardial oxygen consumption compared with controls (P < .05) [2].
• Endothelin-1 (ET-1) is a potent constrictor of bronchial smooth muscle, but there is limited information on its actions on the airway mucociliary clearance in vivo [10].
• ET-1 inhibited baseline mucin secretion (maximum inhibition: 60.3 +/- 4.2%, 50% inhibitory concentration: 0.8 +/- 0.17 nM) [11].
• Twenty-four hours after exposing the cells to graded doses of ET-1 from 1 pM to 1 microM, cell number increased significantly over control in a dose-dependent manner [4].
• 3. Thus in the late gestation ovine fetus endogenous ET-1 modulates basal FHR, CBF and CVR via ETA receptors [12].

Anatomical context of PPET-1

• Importantly, infusion of BQ-123 or ET-1 distal to the common iliac artery did not affect PWV [13].
• In the airways, ET-1 immunoreactivity and mRNA have been detected and localized to the epithelium, smooth muscle, and endothelium in different species, including humans [4].
• In summary, ET-1, acting via ET(A)-receptors, inhibits baseline and ATP-stimulated mucin secretion from ovine airway goblet cells [11].
• This binding was functional as ET-1 promoted mitogenesis of these muscle cells as measured by increased cell number in the absence of serum [4].
• 1. We have proposed that contractile tension of the ductus arteriosus is sustained by a cytochrome P450-linked mechanism acting as a limiting step in the synthesis of endothelin-1 (ET-1) [14].

Associations of PPET-1 with chemical compounds

• Decreased endothelial release of the vasodilator nitric oxide occurs after I/R, but the role of the endothelium-derived vasoconstrictor endothelin-1 (ET-1) in I/R is unknown [2].
• The ET-1 effects were not influenced by pretreatment with either the cyclo-oxygenase inhibitor indomethacin or the leukotriene receptor antagonist MK-571, indicating that ET-1-induced depression in TMV does not involve the activation of prostanoids or peptide leukotrienes [10].
• Big ET-1 contraction, unlike ET-1 contraction, was curtailed by the inhibitor of the ET-1-converting enzyme, phosphoramidon (50 microM) [15].
• 5. ET-1 (0.1-10 nM) had no effect on isolated arteries precontracted with a thromboxane A2 (TXA2) analogue (ONO-11113) and treated with BQ123 (10 microM) [15].
• Hypoxic tone is ascribed primarily to intramural generation of ET-1, while removal of the tonic action of a relaxant may only have an accessory role in the response [15].

Other interactions of PPET-1

• Chronic intrauterine pulmonary hypertension increases preproendothelin-1 and decreases endothelin B receptor mRNA expression in the ovine fetal lung [16].

Analytical, diagnostic and therapeutic context of PPET-1

• In group 3 (n = 8), 10 pmol/L ET-1 was given just before the start of reperfusion [2].
• Dose-response curves to intravenous infusion of ET-1 and phenylephrine were generated for pregnant and nonpregnant sheep [17].
• The objective of the present study was to determine the role of nitric oxide (NO)-endothelin-1 (ET-1) interactions in the acute changes in pulmonary vascular tone after in utero partial constriction of the DA [18].
• After 10 d of ductus arteriosus ligation, immunoreactive ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n = 7) than control (n = 10) lungs (p < 0.05) [19].
• Lung preproET-1 mRNA levels, tissue ET peptide levels, and cellular localization of ET-1 expression were determined by Northern blot analysis, peptide assay, and immunohistochemistry in distal lung tissue from fetal lambs between 70 and 140 days (term = 145 days), newborn lambs, and ewes [20].

References